Linköping University Post Print
Randomised prostate cancer screening trial: 20
year follow-up
Gabriel Sandblom, Eberhard Varenhorst, Johan Rosell, Owe Lofman and Per Carlsson
N.B.: When citing this work, cite the original article.
Original Publication:
Gabriel Sandblom, Eberhard Varenhorst, Johan Rosell, Owe Lofman and Per Carlsson,
Randomised prostate cancer screening trial: 20 year follow-up, 2011, BRITISH MEDICAL
JOURNAL, (342), d1539, .
http://dx.doi.org/10.1136/bmj.d1539
Copyright: Authors
Postprint available at: Linköping University Electronic Press
http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-67564
RESEARCH
Randomised prostate cancer screening trial: 20 year follow-up
Gabriel Sandblom, associate professor,1 Eberhard Varenhorst, professor,2 Johan Rosell, statistician,3 Owe
Löfman, professor,4 Per Carlsson, professor5
1
CLINTEC, Karolinska Institute, 141
86 Stockholm, Sweden
2
Department of Urology,
Linköping University Hospital,
Linköping
3
Oncology Centre, Linköping
University Hospital, Linköping
4
Department of Mathematical
Science and Technology,
Norwegian University of Life
Sciences, 1432 Aas, Norway
5
Center for Health Technology
Assessment, Linköping University,
Linköping
Correspondence to: G Sandblom
[email protected]
Cite this as: BMJ 2011;342:d1539
doi:10.1136/bmj.d1539
ABSTRACT
Objective To assess whether screening for prostate
cancer reduces prostate cancer specific mortality.
Design Population based randomised controlled trial.
Setting Department of Urology, Norrköping, and the
South-East Region Prostate Cancer Register.
Participants All men aged 50-69 in the city of Norrköping,
Sweden, identified in 1987 in the National Population
Register (n=9026).
Intervention From the study population, 1494 men were
randomly allocated to be screened by including every
sixth man from a list of dates of birth. These men were
invited to be screened every third year from 1987 to 1996.
On the first two occasions screening was done by digital
rectal examination only. From 1993, this was combined
with prostate specific antigen testing, with 4 µg/L as cut
off. On the fourth occasion (1996), only men aged 69 or
under at the time of the investigation were invited.
Main outcome measures Data on tumour stage, grade,
and treatment from the South East Region Prostate Cancer
Register. Prostate cancer specific mortality up to 31
December 2008.
Results In the four screenings from 1987 to 1996
attendance was 1161/1492 (78%), 957/1363 (70%),
895/1210 (74%), and 446/606 (74%), respectively.
There were 85 cases (5.7%) of prostate cancer diagnosed
in the screened group and 292 (3.9%) in the control
group. The risk ratio for death from prostate cancer in the
screening group was 1.16 (95% confidence interval 0.78
to 1.73). In a Cox proportional hazard analysis comparing
prostate cancer specific survival in the control group with
that in the screened group, the hazard ratio for death from
prostate cancer was 1.23 (0.94 to 1.62; P=0.13). After
adjustment for age at start of the study, the hazard ratio
was 1.58 (1.06 to 2.36; P=0.024).
Conclusions After 20 years of follow-up the rate of death
from prostate cancer did not differ significantly between
men in the screening group and those in the control
group.
Trial registration Current Controlled Trials,
ISRCTN06342431.
INTRODUCTION
The favourable outcome after radical surgery shown in
a Scandinavian study comparing radical prostatectomy with watchful waiting1 has stimulated the debate
on early detection of prostate cancer, in particular by
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testing for prostate specific antigen. The Prostate,
Lung, Colorectal, and Ovarian (PLCO) Cancer
Screening Trial2 and the European Randomised
Study of Screening for Prostate Cancer (ERSPC)3
were expected to provide final evidence for or against
screening as a method to reduce mortality from prostate cancer. These two large studies, however, did not
show unequivocal benefit from prostate specific antigen screening. The ERSPC trial showed a significant
improvement in cancer specific survival for men in the
screened group but with a high risk of overdiagnosis
and overtreatment.3 The Gothenburg randomised
population based prostate cancer screening trial,4
from one of the centres included in the ERSPC trial,
found a risk ratio for prostate cancer specific death
similar to that found in the ERSPC trial. The PLCO
trial, on the other hand, did not show any benefit from
screening,2 probably because of a large degree of crossover contamination. Follow-up in the PLCO might
also have been too short to provide reliable data on
mortality.
In 1987 a randomised controlled trial on screening
for prostate cancer was started in Norrköping, Sweden.
The study was started before prostate specific antigen
testing was established as a method of screening so at
the first two screening sessions only digital rectal examination was used. From 1993 this was combined with a
prostate specific antigen test. The feasibility of a screening programme for prostate cancer has previously
been reported.5 We have also previously presented
data on the reliability of digital rectal examination,6
the cost effectiveness of screening for prostate
cancer,7 8 and the clinical consequences of screening.9
Here we report on mortality 20 years after the start of
study.
METHODS
The design of the study has been described elsewhere.9
In 1987 all men aged 50-69 in Norrköping, Sweden,
were identified in the National Population Register.
The total study population was 9026 men. From this
population, 1494 men were randomly allocated to be
screened by including every sixth man from a list of
dates of birth. The 7532 remaining men constituted
the control group. All men in the study group were
contacted by mail one week before each examination.
Information regarding the study was also spread by
page 1 of 6
RESEARCH
Control group (n=7532)
Intervention group (n=1494)
Screening with DRE in 1987 (n=1161),
13 cancers detected at screening
Interval cancers (n=5)
Screening with DRE in 1990 (n=957),
7 cancers detected at screening
Interval cancers (n=8)
Screening with DRE and PSA in 1993 (n=895),
17 cancers detected at screening
Interval cancers (n=5)
Screening with DRE and PSA in 1996, only men
aged <70 (n=606), 6 cancers detected at screening
Interval cancers (n=24)
Follow-up of cancers detected up to 31 December 1999
Cancers detected in
control group up to
31 December 1999 (n=292)
Interval cancers (n=42)
Cancers detected
at screening (n=43)
Follow-up of survival up to 31 December 2008
Fig 1 | Flow chart of study group enrolment. DRE=digital rectal examination, PSA=prostate
specific antigen
local media. The sample size was calculated to allow us
to assess the acceptance and feasibility of a prostate
cancer screening programme.
At the first screening session in 1987 a specialist in
urology and a general practitioner performed the digital rectal examinations. This double examination was
done to determine the reliability of the examination
between observers.6 At subsequent sessions only general practitioners performed the examinations. At the
third and fourth screening sessions, in 1993 and 1996,
digital rectal examination was combined with a test for
prostate specific antigen, with concentrations of >4 µg/
L as the cut off. With the exception of men who had
emigrated, the cohort allocated to screening remained
the same for the first three sessions. In the fourth session, only men aged 69 or under at the time of the investigation were invited, which left a total of 606 men. All
men, including those who did not participate in the
fourth session, were included in the final analysis.
When the results of the digital rectal examination or
prostate specific antigen test led to a suspicion of prostate cancer, the man underwent fine needle aspiration
biopsy. The biopsy samples were taken from the peripheral zone of the apex, mid-prostatic region, and
bases of both lateral lobes according to a sextant distribution. Directed biopsy samples were also taken in
men in whom a nodule was palpated. If the biopsy
page 2 of 6
result was negative, information was sent by mail.
Men with positive cytology result were followed up
by a urologist and treated according to the standardised management programme in the region. Investigations of men with prostate cancer included testing for
prostate specific antigen, transrectal ultrasonography,
and bone scan. Depending on the tumour stage and the
general condition of the patient, men were offered
radiotherapy or radical prostatectomy if it was considered possible to prolong survival.
The trial was made possible by the system of personal registration numbers,10 each number being unique
for each Swedish citizen, making it possible to trace all
participants in the study in the population register, the
South-East Region Prostate Cancer Register, and the
Central Death Register.11
All cases of prostate cancer, whether detected in the
screened or in the non-screened cohort, were registered in the South-East Region Prostate Cancer Register. This register is an extension of the National Cancer
Register, which was founded in 1958 to enable continuous surveillance of the incidence of all oncological
diseases. The personal registration numbers are used
to link the South-East Region Prostate Cancer Register
with the National Cancer Register. Whenever a new
case of prostate cancer is registered in the South-East
Region, the physician responsible for the patient submits a report according to a standardised protocol,
including tumour stage according to the tumour,
node, metastases (TNM) classification, tumour grade,
and treatment, to the regional oncological centre for
recording in the South-East Region Prostate Cancer
Register.
Figure 1 shows the trial enrolment and study group
assignment. Date of diagnosis, TNM categories,
tumour grade, and treatment were registered in the
South-East Region Prostate Cancer Register for all
men with a diagnosis of prostate cancer in the screened
and the non-screened cohort. All patients with cancer
were treated according to a standardised management
programme for prostate cancer common to the South
East Region. Date and cause of death were also
Cumulative survival
All men in Norrköping aged 50-69 in 1987 without diagnosis of prostate cancer (n=9026)
Every sixth man randomised to screening
1.0
Screened
Controls
0.8
0.6
0.4
0.2
0
0
Men at risk:
Screened
Controls
5
10
15
81
275
68
216
50
135
20
25
Survival time (years)
20
72
Fig 2 | Kaplan-Meier curves of overall survival for men
diagnosed with prostate cancer in control group (n=292) and
screened group (n=85). Log rank test P=0.14
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RESEARCH
Table 1 | Baseline data and mortality in men allocated to screening for prostate cancer or no
screening (control group)
No screening group
Screening group
7532
1494
50-54
1790
357
55-59
1809
360
60-64
2004
393
65-69
1929
384
No (%) of prostate cancers diagnosed, 1 January 1987
to 31 December 1999
292 (3.9)
85 (5.7)*
Mean (SD) age at diagnosis (years)
69.7 (5.7)
68.1 (5.6)†
No of men (excluding men with prostate cancer already diagnosed)
Age (years):
*43 (2.9%) detected at screening; 42 (2.58%) interval cancers.
†66.5 (5.2) in men with cancer detected at screening; 69.9 (5.5) in men with interval cancers.
recorded in the register when applicable. The Central
Death Register was checked for deaths not registered
in the South-East Region Prostate Cancer Register. In
September 2009 cause of death was registered in a
blinded review of the patients’ records for all men
who died. All men in whom cancer was diagnosed up
to 31 December 1999 were included in the analysis.
Survival was followed until 31 December 2008.
Cumulative survival
Statistics
All analyses were performed based on intention to
screen comparisons. We used Cox proportional
hazard modelling to estimate hazard ratios for death
from prostate cancer, with age and group allocation
(screening/control) as covariates. To investigate
whether the detection rate and subsequent mortality
changed after the introduction of prostate specific antigen testing as a screening tool, we also tested a model
with diagnosis before 1993 versus diagnosis after 1993
as a dichotomous time varying covariate. We used log
rank to test differences in total and prostate cancer specific survival. The difference in deaths from prostate
cancer between the two groups was tested by determining the risk ratio for prostate cancer specific death.
We also performed a subgroup analysis of men with
a diagnosis in 1993 or later—that is, from the time that
1.0
Screened
Controls
0.8
0.6
0.4
0.2
0
0
Men at risk:
Screened
Controls
5
10
15
81
275
68
216
50
135
20
25
Survival time (years)
20
72
Fig 3 | Kaplan-Meier curves of prostate cancer specific survival
for men diagnosed with prostate cancer in control group
(n=292) and screened group (n=85). Log rank test P=0.065
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prostate specific antigen testing was introduced in the
screening arm. All analyses were performed with SPSS
18.0.
The main outcome measure was the prostate cancer
specific death risk ratio. The study was designed to
detect a plausible reduction of prostate cancer specific
mortality within 20 years from the start of the study
from 1.5% to 1.0% in the screening group. A total of
1050 patients in the screening group would be required
to detect this difference (80% power, two sided 5% significance level). To allow for non-compliance in the
screening group and contamination in the control
group, 1400 men were included in the screening group.
No interim analyses with mortality as end point were
performed.
RESULTS
In 1987, 1161 of 1492 (78%) invited men underwent
screening. The numbers were 957/1363 (70%) in 1990
and 895/1210 (74%) in 1993. In 1996, men born before
1927 (n=512) were not invited to screening, leaving
606 men born 1927-37. Of these, 446 (74%) attended
the screening. The median follow-up time was
75 months.
Eighty five cases (5.7%) of prostate cancer were diagnosed in the screened group and 292 (3.9%) in the control group (table 1). In the intervention group, 43
tumours were found at screening and 42 in the interval
between examinations (table 2). The percentage of
men with localised tumours (T1-2, N0/NX, M0) was
significantly higher in the screened group (56.5%)
than in the control group (26.7%, P<0.001). The rates
of non-localised tumours were 37/1494 (2.5%) in the
screening group and 213/7532 (2.8%) in the control
group (P=0.44).
The prostate cancer specific mortality was 30/85
(35%) for men with prostate cancer diagnosed in the
screening group and 130/292 (45%) for men with prostate cancer diagnosed in the control group. The overall
mortality for men with prostate cancer was 69/85
(81%) in the screening group and 252/292 (86%) in
the control group. The median cancer specific survival
was 201 months in the screened group and 133 months
in the control group. The risk ratio for death from prostate cancer was 1.16 (95% confidence interval 0.78 to
1.73).
The log rank test did not show a significantly longer
prostate cancer survival (P=0.065) or overall survival
(P=0.14) for men with prostate cancer diagnosed in the
screening group (figs 2 and 3). Figure 4 shows the
cumulative mortality. In a Cox proportional hazard
analysis, the hazard ratio for death from prostate cancer was 1.23 (0.94 to 1.62; P=0.13) and 1.58 (1.06 to
2.36; P=0.024) after adjustment for age at start of the
study. With the addition of the period of diagnosis as
1987-92 or 1993-9 as a dichotomous time dependent
variable and adjustment for age at the start of the study,
the hazard ratio was 1.59 (1.07 to 2.38; P=0.022). The
period of diagnosis as a time dependent variable was
not found to be a significant covariate in univariate
analysis.
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RESEARCH
Table 2 | Distribution of tumour stage, tumour grade, and treatment in men with prostate cancer according to allocation to
screening or no screening (control). Figures are numbers (percentages)
Screening group
No screening group
All cancers
Cancers detected at screening
Interval cancers
Localised tumours (T1-2, N0/NX, and M0)
78 (26.7)
48 (56.5)
36 (83.7)
12 (28.6)
Advanced tumours (T3-4, N1, or MX/M1)
213 (73.3)
37 (43.5)
7 (16.3)
30 (71.4)
Tumour stage:
Tumour grade:
G1
94 (32.2)
43 (50.6)
24 (55.8)
19 (45.2)
G2
149 (51.0)
31 (36.5)
19 (44.2)
12 (28.6)
G3
43 (14.7)
11 (12.9)
0 (0)
11 (26.2)
6 (2.1)
0 (0)
0 (0)
0 (0)
Watchful waiting
101 (34.6)
37 (43.5)
21 (48.8)
16 (38.1)
Hormonal treatment
147 (50.3)
27 (31.8)
4 (9.3)
23 (54.8)
Radical prostatectomy
23 (7.9)
16 (18.8)
14 (32.6)
2 (4.8)
Brachytherapy
3 (1.0)
1 (1.2)
0 (0)
1 (2.4)
External radiotherapy
15 (5.1)
4 (4.7)
4 (9.3)
0 (0)
Not registered
3 (1.0)
0 (0)
0 (0)
0 (0)
GX/tumour grade not recorded
Treatment:
Strength of this study
The high compliance, uniform treatment, and complete data on tumour stage, tumour grade, and cause
of death provided by the South-East Region Prostate
Cancer Register and the Central Death Register all
give strength to our findings. The personal registration
number unique for each Swedish citizen10 minimises
the risk of dropouts and incomplete data because of
change of address.
The completeness of the National Cancer Register
has also been found to be high,13 which supports the
validity of the South-East Region Prostate Cancer Register. A validation of the South-East Region Prostate
Cancer Register showed a high accuracy and completeness for all variables included.14
The extended prostate cancer registration, which
covered the screened group as well as the control
group, provided data on tumour stage, tumour grade,
treatment, and mortality for both groups.14 All men
with a diagnosis of prostate cancer, whichever group
they were allocated to, underwent the same standardised management programme. Uniform principles
for registration, evaluation, and treatment decision
minimise the risk of bias caused by local variations in
management. All men in the screening group as well as
in the control group were managed in the same urology
unit. The incidence of prostate cancer was higher in the
screening group, probably because of detection of a
page 4 of 6
larger number of indolent tumours that do not reduce
prostate cancer specific survival or overall survival.
Comparison with other studies
Opportunistic screening for prostate specific antigen is
not practised as widely in Sweden as in the United
States.15-17 Until 1994, less than one test per man aged
50 or older was performed in Sweden.18 The relatively
low level of such testing in the background population
reduced the chance of contamination as well as the prevalence of undetected indolent tumours in the screening group before the start of the study. The study
started before testing was introduced in clinical
practice,18 which could have increased the lead time
even more. Until 1987, prostate cancer was diagnosed
almost exclusively at presentation with symptoms or
incidentally at histopathological examination after
transurethral prostate resection. The pre-screening
prevalence of asymptomatic low grade tumours was
therefore low.
Although screening with digital rectal examination
and prostate specific antigen is an effective method for
detecting early stages of prostate cancer, the high rate
of overdiagnosis has to be considered before
Cumulative mortality
DISCUSSION
In this randomised controlled trial, screening for prostate cancer did not seem to have a significant effect on
mortality from prostate cancer after 20 years of followup. The relatively high cancer specific mortality seen in
men with localised prostate cancer if they are followed
up for long enough12 makes not only the large sample
size but also a sufficiently long follow-up time prerequisites for accurate interpretation of mortality data.
1.0
0.8
Screened
Controls
0.6
0.4
0.2
0
0
5
10
15
20
25
Years since diagnosis
Fig 4 | Cumulative rates of prostate cancer specific mortality
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RESEARCH
WHAT IS ALREADY KNOWN ON THIS TOPIC
Previous studies have questioned the short term benefit of prostate cancer screening, but
these lack long term follow-up
WHAT THIS STUDY ADDS
In a randomised controlled study on a population with little background opportunistic
screening, complete registration of tumour stage, tumour grade, and treatment of both
screening and control groups showed that the risk for overdetection and overtreatment in the
screening group is considerable
widespread introduction of routine prostate cancer
screening.19 At the start of this trial, digital rectal examination and fine needle aspiration biopsy were used for
tumour detection. Despite the fact that these methods
have a lower sensitivity than prostate specific antigen
testing and ultrasound guided biopsy, there was a significant shift towards detection of localised tumours in
the intervention group.9 The rate of diagnosis in the
screened group, however, was lower than in the
PLCO and ERSPC trials.2-4
Disease specific mortality is one of the most sensitive
measures of the aggressiveness of a disease and the
effectiveness of treatment. Determination of disease
specific mortality, however, requires accurate determination of the underlying cause of death. In a review of
the medical records of patients in the South-East
Region Prostate Cancer Register, the validity of the
death certificates that constitute the base for the cause
of death was shown to be high.20 This also supports the
outcome of our study as we determined disease specific
mortality from the South-East Region Prostate Cancer
Register. Although the data in the ERSPC, as well as
trials, have been carefully validated,21 the criteria for
defining death in prostate cancer are more vaguely
defined.
The impact of screening on stage shift has been
described in a previous report.9 The tumours in the
screening group were smaller and more often localised
than in the control group. In contrast with the PLCO
and ERSPC trials,21 we had complete data on tumour
stage for all men in the control group and the screened
group. The screening had high acceptance in the population and a reasonable cost.7 8 The actual cost of the
tests, however, is only a part of the total cost of
screening.8 22 The total healthcare costs for prostate
cancer treatment and other relevant costs in healthcare
and in society should also be taken into consideration
before the introduction of a widespread screening
programme.
The population size in our study was smaller than the
PLCO and ERSPC trials, but the longer follow-up,
high attendance, and low rate of contamination caused
the power to reach a similar level. The risk ratio for
prostate cancer specific death in our study (1.16, 0.78
to 1.73) was close to that found in the PLCO trial (1.13,
0.75 to 1.70). The confidence interval of the risk ratio
was narrow enough to conclude that screening and
treatment of men with tumours detected through
screening as practised in the present study is unlikely
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to reduce mortality from prostate cancer by more than
a third. Though screening could lead to a reduction of
up to a third in mortality from prostate cancer, this
would be at the risk of overdetection and
overtreatment.9
Although the outcomes are somewhat contradictory, the results of our study and the PLCO and
ERSPC studies indicate that, whether or not there
might be a benefit from prostate cancer screening, a
high rate of overdiagnosis is unavoidable.2-4 In the
ERSPC trial, it was estimated that screening for prostate cancer could advance the diagnosis by 10 years.
Half of the cancers detected by screen would not
have been diagnosed in the absence of screening.22 23
To prevent one death from cancer, 1410 men would
need to be screened and 48 treated.3
Policy implications
Before undergoing prostate specific antigen testing,
asymptomatic men should be informed about the
potential hazards of treatment with curative intent in
case prostate cancer is diagnosed. These include erectile dysfunction, urinary incontinence, and bowel
symptoms. The discomfort associated with prostate
biopsy and the psychological effects of false positive
results should also be considered.24 The next goal for
prostate screening should rather be to find ways of discriminating indolent tumours from high risk tumours
and to develop less aggressive treatment for indolent
tumours25 rather than to optimise sensitivity of the
diagnostic tests.
Conclusions
The risk ratio for prostate cancer specific death did not
indicate significant benefit from prostate cancer
screening. Although the population size in our study
is not sufficient to draw definite conclusions, the
power is sufficient to show major differences in prostate cancer specific survival.
Contributors: GS drafted the manuscript, with contributions from all other
coauthors. EV organised the screening programme with OL and PC. EV
also conceived the study design. JR did all the analyses. GS is guarantor.
Funding: This study was funded by the Research Council of the SouthEast Region of Sweden (No F97-318), the Swedish Cancer Foundation,
and the County Council of Östergötland.
Competing interests: All authors have completed the Unified Competing
Interest form at www.icmje.org/coi_disclosure.pdf (available on request
from the corresponding author) and declare: no support from any
organisation for the submitted work; no financial relationships with any
organisations that might have an interest in the submitted work in the
previous three years; no other relationships or activities that could appear
to have influenced the submitted work.
Ethical approval: This study was approved by the institutional review
board of Linköping, Sweden, 1992. Participants gave informed consent
for data sharing.
Data sharing: Technical appendix, statistical code, dataset and the full
study protocol are available from [email protected].
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Accepted: 24 December 2010
BMJ | ONLINE FIRST | bmj.com
